ABSTRACT Blood cells of an adult vertebrate are continuously generated by hematopoietic stem cells (HSCs) that originate during embryonic life within the aorta-gonad-mesonephros region. There is now compelling in vivo evidence that HSCs are generated from aortic endothelial cells and that this process is critically regulated by the transcription factor Runx1. By time-lapse microscopy of Runx1-enhanced green fluorescent protein transgenic zebrafish embryos, we were able to capture a subset of cells within the ventral endothelium of the dorsal aorta, as they acquire hemogenic properties and directly emerge as presumptive HSCs. These nascent hematopoietic cells assume a rounded morphology, transiently occupy the subaortic space, and eventually enter the circulation via the caudal vein. Cell tracing showed that these cells subsequently populated the sites of definitive hematopoiesis (thymus and kidney), consistent with an HSC identity. HSC numbers depended on activity of the transcription factor Runx1, on blood flow, and on proper development of the dorsal aorta (features in common with mammals). This study captures the earliest events of the transition of endothelial cells to a hemogenic endothelium and demonstrates that embryonic hematopoietic progenitors directly differentiate from endothelial cells within a living organism.

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Hematopoiesis is a key process that leads to the formation of all blood cell lineages from a specialized, multipotent cell, named the Hematopoietic Stem Cell (HSC). During development, the embryo produces several waves of hematopoiesis that produce specialized subsets of hematopoietic cells. Tissue interactions and cell signaling play an essential role in developmental hematopoiesis by allowing the formation of hematopoietic and endothelial cells (EC) from the mesoderm in particular in the yolk sac and by instructing the different generations of hematopoietic cells (HC). The embryonic aorta is another site wherein tissue interaction is essential for the production of the first HSCs that is achieved from a specialized subset of hemogenic endothelial cells. This production is tightly time- and space-controlled with the transcription factor Runx1 and the Notch signaling pathway playing a key role in this process and the surrounding tissues controlling the aortic shape and fate. Here we shall briefly review how hemogenic EC differentiate from the mesoderm, how the different aortic components assemble coordinately to establish the dorso-ventral polarity resulting in the initiation of Runx1 expression in hemogenic EC and the initiation of the hematopoietic program through modulation of the Notch-Runx1 axis. These data should help elucidate the first steps in HSC commitment and bring further insights into the manipulation of adult HSCs.

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Chromosomal translocations involving fusions of the human ETV6 (TEL1) gene occur frequently in hematological malignancies. However, a detailed understanding of the normal function of ETV6 remains incomplete. This study has employed zebrafish as a relevant model to investigate the role of ETV6 during embryonic hematopoiesis. Zebrafish possessed a single conserved etv6 orthologue that was expressed from 12 hpf in the lateral plate mesoderm, and later in hematopoietic, vascular and other tissues. Morpholino-mediated gene knockdown of etv6 revealed the complex contribution of this gene toward embryonic hematopoiesis. During primitive hematopoiesis, etv6 knockdown resulted in reduced levels of progenitor cells, erythrocyte and macrophage populations, but increased numbers of incompletely differentiated heterophils. Definitive hematopoiesis was also perturbed, with etv6 knockdown leading to decreased erythrocytes and myeloid cells, but enhanced lymphopoiesis. This study suggests that ETV6 plays a broader and more complex role in early hematopoiesis than previously thought, impacting on the development of multiple lineages.

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